Glucokinase (GK)(ATP: D-hexose 6-phosphotransferase, EC 2.7.1.1) is one of 4 types of hexokinase (hexokinase IV) in mammals. Hexonase is an enzyme acting in the first stage of a glycolytic pathway which catalyzes the reaction from glucose to glucose 6-phosphate. Occurrence of glucokinase is localized mainly in liver and the beta cells of pancreas, in which glucokinase controls the rate-determining step of glucose metabolism, whereby it plays an important role in the generalized saccharometabolism. Glucokinase in liver and that in the beta cells of pancreas are the same in their enzymatic properties, though the sequences of the N-terminal 15 amino acids are different from each other due to the difference of splicing. In 3 types of hexokinase (I, II, and III) other than glucokinase, the enzyme activities are saturated at a 1 mM or lower concentration of glucose, whereas the Km of glucokinase for glucose is 8 mM, which value is proximate to the physiological blood sugar level. Therefore, the intracellular glucose metabolism is accelerated through glucokinase in response to the change of blood sugar level from normal (5 mM) to postprandial elevation (10-15 mM).
About 10 years ago, a hypothesis has been proposed that glucokinase works as a glucose sensor in the beta cells of pancreas or liver (Garfinkel D, et al., “Computer modeling identifies glucokinase as glucose sensor of pancreatic beta-cells”, American Journal Physiology, 247, 3Pt2, 1984, P. 527-536). From the recent results in mice in which glucokinase has been genetically engineered, it has been found that glucokinase in fact has an important role in the generalized homeostasis of glucose. Though mice of which the glucokinase gene has been destroyed result in death shortly after birth (Grupe A, et al., “Transgenic knockouts reveal a critical requirement for pancreatic beta cell glucokinase in maintaining glucose homeostasis”, Cell, 83, 1995, P. 69-78, the blood sugar level is decreased in normal and diabetic mice in which glucokinase has been generated in excess (Ferre T, et al., “Correction of diabetic alterations by glucokinase”, Proceedings of the National Academy of Sciences of the U.S.A., 93, 1996, P. 7225-7230). With increase of the glucose concentration, the reactions of the pancreatic beta cells and hepatocytes move toward decreasing the blood sugar level though the degree is different respectively. The pancreatic beta cells work to secrete much more insulin, and on the other hand the liver uptakes sugar and store it as glycogen, resulting in decrease of sugar release.
Thus, the change of the enzymatic activity of glucokinase plays an important role in mammalian glucose homeostasis through liver and the beta cells of pancreas. In a case of causing juvenile diabetes which is called MODY2 (maturity-onset diabetes of the young), it has been found that a mutation occurs in the glucokinase gene and decrease of the glucokinase activity increases the blood sugar level (Vionnet N, et al., “Nonsense mutation in the glucokinase gene causes early-onset non-insulin-dependent diabetes mellitus”, Nature Genetics, 356, 1992, P. 721-722). It has also been found that there is a kindred which has a mutation increasing the glucokinase activity and shows hypoglycemia (Glaser B, et al., “Familial hyperinsulinism caused by an activating glucokinase mutation”, New England Journal Medicine, 338, 1998, P. 226-230).
This means that glucokinase works as a glucose sensor in human and plays an important role in glucose homeostasis. On the other hand, it is considered that in a large number of the II-type diabetic patients it will be possible to regulate the blood sugar level utilizing a system of glucokinase sensor. The glucokinase-activating substances are expected to have an effect of accelerating the insulin secretion in the pancreatic beta cells and an effect of accelerating the sugar uptake and inhibiting the sugar release in liver, and they are considered useful as therapeutic agents in the II-type diabetic patients.
In recent years, it has been elucidated that the occurrence of glucokinase of the pancreatic beta cell type is localized in the brain of rats, particularly in the feeding center (ventromedial hypothalamus; VMH). It has long been considered that about 20% of the neurocytes in VMH, called the glucose responsive neuron, have an important role in control of body weight. Feeding of rats is decreased when glucose is administered into the brain, while inhibition of the glucose metabolism by intracerebral administration of a glucose analog, glucosamine, causes hyperphagia. From electrophysiological experiments, it has been recognized that the glucose responsive neuron is activated in response to the physiological change of glucose concentration (5-20 mM), but its activity is inhibited by inhibiting the glucose metabolism with glucosamine. The same mechanism through glucokinase has been assumed in the sensor system for the glucose concentration in VHM as in the insulin secretion in the pancreatic beta cells. Therefore, in addition to the action in the liver and pancreatic beta cells, a glucokinase-activating substance in VMH is expected to improve not only the blood sugar lever but also obesity which is a problem in a large number of II-type diabetic patients.
As seen from the above description, glucokinase-activating compounds are useful as therapeutic agents and/or preventive agents for diabetes mellitus or for chronic diabetic complications such as retinopathy, nephropathy, neurosis, ischemic heart disease or arteriosclerosis, as well as for obesity.
As for a compound having a pyridine skeleton and an amide linkage attached to the pyridine skeleton which are contained in the compounds (I) of the invention, the following compound represented by the structural formula (IV) has been described (see, for example, Japanese Laid-Open Patent Application No. 5-213382).

In the compound (1V) described in Japanese Laid-Open Patent Application No. 5-213382, however, the location of the C═N and the amide linkage in the isoxazole group is different from that of the compounds of the invention. In addition, it is also different in that while the utility of the compounds of the invention includes diabetes mellitus, the utility described in Japanese Laid-Open Patent Application No. 5-213382 relates to herbicide.
As for the structurally analogous compounds having the utility for diabetes mellitus, the following compounds represented by the formulae (V):
and (VI):
have been described (see, for example, Published Japanese Translation of PCT International Publication No. 2001-522834).
One of the utility of the compounds described in the Published Japanese Translation of PCT International Publication No. 2001-522834 is for diabetes mellitus, the same as that of the compounds (I) of the present invention.
The compound (V) or (VI) described in the Published Japanese Translation of PCT International Publication No. 2001-522834 and the compounds (I) of the present invention have a pyridine skeleton in common as the fundamental skeleton and an amide linkage on the pyridine ring.
It is different, however, in that the compounds (I) of the present invention have a substituent at the 6 position of the pyridine ring, while the compound (V) or (VI) has no substituent at the 6 position of the pyridine ring.
In addition, it is also different that the compounds (I) of the invention have an amide linkage adjacent to the nitrogen atom constituting the pyridine ring, while the compound (VI) described in Published Japanese Translation of PCT International Publication No. 2001-522834 has an amide linkage at the position separated by one carbon from the nitrogen atom constituting the pyridine ring. Moreover, the location of the amide linkage relative to the C═N moiety of the pyridine ring corresponding to the ring B in the compounds (I) of the present invention is different from that of the compound (VI) of the Published Japanese Translation of PCT International Publication No. 2001-522834.
As for a compound having the same pyridine-2-carboxamide skeleton as the compounds (I) of the present invention, the compound of the formula (VII):
has been described (see, for example, WO01/81345). However, the location of the amide linkage relative to the nitrogen atom of 1H-pyrazolo[3,4-b]pyridine-4-yl which is attached to the nitrogen atom of the amide linkage in the compound (VII) is different from the location of the amide linkage relative to the C═N in the ring B of the compounds (I) of the present invention. In addition, it is different that, while the 3 and 6 positions of the pyridine skeleton in the formula (VII) are occupied by hydrogen atoms, those of the compounds (I) are occupied by other groups than hydrogen atoms. Thus, the compound of the formula (VII) is different from the compounds (I) of the present invention in the entire structure.
Therefore, the compounds (I) of the present invention are different from the compound described in WO01/81345 in the aspect of the substituent attached to the pyridine skeleton, though both compounds have the pyridine-2-carboxamide as fundamental skeleton. Thus, the compounds (I) are different from the compound (VII) in total.
The purpose of the invention is to provide a therapeutic agent and/or preventive agent for diabetes mellitus which can bind to glucokinase to increase the glucokinase activity, as well as an anti-obesity agent which activates glucokinase to stimulate the satiety center.
As mentioned above, it is advantageous that the compounds of the invention have a better drug effect than the existing diabetic agents and provide a possibility of resulting in development of new drug effects which have not been possessed by the existing diabetic agents.
The present inventors, accordingly, worked assiduously to develop a new diabetic agent which has a better new drug effect than the existing diabetic agents based on a mechanism of action that is different from that of the existing drugs. As a result, they have found that the compounds represented by the formula (I) have a glucokinase-activating effect. Thus, the invention has been completed.